The chemistry of the carbon-transition metal double and triple bond: Annual survey covering the year 2013☆

In carbonylative benzannulations, feedstock carbon monoxide is converted to a benzene ring, which is one of the most fundamentally important and common rings in natural products and pharmaceutical compounds. Carbon monoxide, however, is rather inert in the absence of transition metals. Historically, carbonylative benzannulations have been mediated by stoichiometric chromium and iron in the form of Fischer carbenes. Recently, a number of transition metal-catalyzed carbonylative benzannulations have been developed, and almost all of them involve rhodium catalysts. This review will briefly discuss the mechanism and applications of carbonylative benzannulations involving Fischer carbenes and compare them with the more recent transition metal-catalyzed processes, including [3 + 2 + 1] cycloadditions, [5 + 1] cycloadditions, and other less common cycloadditions.

Transition metal mediated carbonylative benzannulations

Recent Advances in the Synthesis of Spiro-β-Lactams and Spiro-δ-Lactams

Natural products from medicinal plants have always attracted a lot of attention due to their diverse and interesting therapeutic properties. We have employed the principles of green chemistry involving isomerization, coupling and condensation reaction to synthesize a class of compounds derived from eugenol, a naturally occurring bioactive phytophenol. The compounds were characterized structurally by 1H-, 13C-NMR, FT-IR spectroscopy and mass spectrometry analysis. The purity of compounds was detected by HPLC. The synthesized compounds exhibited anti-cancer activity. A 10–12-fold enhancement in efficiency of drug molecules (~ 1 µM) was observed when delivered with graphene oxide (GO) as a nanovehicle. Our data suggest cell death via apoptosis in a dose-dependent manner due to increase in calcium levels in specific cancer cell lines. Interestingly, the benzoxazine derivatives of eugenol with GO nanoparticle exhibited enhanced therapeutic potential in cancer cells. In addition to anti-cancer effect, we also observed significant role of these derivatives on parasite suggesting its multi-pharmacological capability.

Integrative natural medicine inspired graphene nanovehicle-benzoxazine derivatives as potent therapy for cancer.

Malaria remains a global public health problem due to the uphill fight against the causative Plasmodium parasites that are relentless in developing resistance. Indole-based antiplasmodial compounds are endowed with multiple modes of action, of which inhibition of hemozoin formation is the major mechanism of action reported for compounds such as cryptolepine, flinderoles, and isosungucine. Indole-based compounds exert their potent activity against chloroquine-resistant Plasmodium strains by inhibiting hemozoin formation in a mode of action different from that of chloroquine or through a novel mechanism of action. For example, dysregulating the sodium and osmotic homeostasis of Plasmodium through inhibition of PfATP4 is the novel mechanism of cipargamin. The potential of developing multi-targeted compounds through molecular hybridization ensures the existence of indole-based compounds in the antimalarial pipeline.

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Indole: The After Next Scaffold of Antiplasmodial Agents?

Natural products offer an abundant source of diverse novel scaffolds that inspires development of next generation anti-malarials. With this vision, a library of scaffolds inspired by natural biologically active alkaloids was synthesized from chiral bicyclic lactams with steps/scaffold ratio of 1.7:1. On evaluation of library of scaffolds for their growth inhibitory effect against malaria parasite we found one scaffold with IC50 in low micro molar range. It inhibited parasite growth via disruption of Na+ homeostasis. P-type ATPase, PfATP4 is responsible for maintaining parasite Na+ homeostasis and is a good target for anti-malarials. Molecular docking with our scaffold showed that it fits well in the binding pocket of PfATP4. Moreover, inhibition of Na+-dependent ATPase activity by our potent scaffold suggests that it targets parasite by inhibiting PfATP4, leading to ionic imbalance. However how ionic imbalance attributes to parasite's death is unclear. We show that ionic imbalance caused by scaffold 7 induces autophagy that leads to onset of apoptosis in the parasite evident by the loss of mitochondrial membrane potential (ΔΨm) and DNA degradation. Our study provides a novel strategy for drug discovery and an insight into the molecular mechanism of ionic imbalance mediated death in malaria parasite.

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Rajanikanth Mamidala

Papers

Natural Product Inspired Novel Indole based Chiral Scaffold Kills Human Malaria Parasites via Ionic Imbalance Mediated Cell Death.

Diversity Oriented Synthesis of Macrocyclic Diaryl Ethers by Dötz Benzannulation